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WO2001040165A1 - Forme cristalline d'acide propanoique 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(s)-2-ethoxy - Google Patents

Forme cristalline d'acide propanoique 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(s)-2-ethoxy Download PDF

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Publication number
WO2001040165A1
WO2001040165A1 PCT/SE2000/002379 SE0002379W WO0140165A1 WO 2001040165 A1 WO2001040165 A1 WO 2001040165A1 SE 0002379 W SE0002379 W SE 0002379W WO 0140165 A1 WO0140165 A1 WO 0140165A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystalline form
compound
formula
ethoxy
tert
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/SE2000/002379
Other languages
English (en)
Inventor
Maria Boije
Martin Bohlin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE9904417A external-priority patent/SE9904417D0/xx
Priority claimed from SE0001422A external-priority patent/SE0001422D0/xx
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Priority to AU20346/01A priority Critical patent/AU2034601A/en
Publication of WO2001040165A1 publication Critical patent/WO2001040165A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring

Definitions

  • the present invention relates to crystalline forms of the compound 3- ⁇ 4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl ⁇ -(S)-2-ethoxy propanoic acid, shown by the formula I (set out below),
  • the invention also concerns methods of treating one or more metabolic diseases, particularly those associated with Insulin Resistance Syndrome, and the use of a crystalline form of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a medicament for therapeutic use in one or more metabolic diseases.
  • the invention further concerns pharmaceutical compositions containing a crystalline form of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as active ingredient, as well as processes for the manufacture of a crystalline form of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the drug substance In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance in obtaining a commercially viable manufacturing process, and also for subsequent manufacture of pharmaceutical formulations comprising the active compound.
  • the drug substance, and compositions containing it should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility). Moreover, it is also important to be able to provide drug in a form which is as chemically pure as possible.
  • Amorphous materials may present significant problems in this regard. For example, such materials are typically more difficult to handle and to formulate compared with crystalline forms, provide for unreliable solubility, and are often found to be unstable and chemically impure.
  • Insulin Resistance Syndrome refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinaemia, possible type 2 diabetes mellitus, arterial hypertension, central (visceral) obesity, dyslipidaemia observed as deranged lipoprotein levels typically characterised by elevated VLDL (very low density lipoproteins) and reduced HDL (high density lipoproteins) concentrations and reduced fibrinolysis.
  • VLDL very low density lipoproteins
  • HDL high density lipoproteins
  • the present invention relates to a crystalline solid form of the compound of formula I.
  • Significant advantages can arise when the compound of formula I can be isolated in a crystalline form, for example, in the manufacture of the compound to the purity levels and uniformity required for regulatory approval and for ease and uniformity of formulation. It is therefore highly desirable to find a novel crystalline form of the compound.
  • a crystalline form of the compound of formula I can be defined by reference to its melting point, powder X-ray diffraction pattern and single crystal X-ray data.
  • the melting point of the crystalline form of the compound of formula I generally depends on the level of purity and may be determined by conventional procedures well known in the art, for example, by differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • the crystalline form of the compound of formula I has a melting point which is in the range 102-112°C, for example about 105-109°C, when it is substantially or essentially in the anhydrous form.
  • the crystalline form of the compound of formula I when it is substantially or essentially in the anhydrous form, has an X-ray powder diffraction pattern containing specific peaks of high intensity at 9.3, 5.5, 4.89. 4.83. 4.67, 4.22. 3.82 and 3.62 A. Additional specific peaks of lower relative intensity to the first peaks are at 14.4, 6.0, 5.7, 4.99, 4.53, 4.46, 4.33, 4.28, 3.99, 3.70, 3.54, 3.47, 3.07 and 2.59 A.
  • Crystalline compound of formula I may be obtained from a non-crystalline form of the compound of formula I, by crystallisation from a suitable solvent (including organic solvents, aqueous solutions and mixtures thereof), such as isooctane, butylacetate and toluene, or a mixture of solvents, such as a mixture of ethanol and water.
  • a suitable solvent including organic solvents, aqueous solutions and mixtures thereof
  • solvents such as a mixture of ethanol and water.
  • seeding with crystalline compound of formula I may be required.
  • Crystallisation of the compound from an appropriate solvent system may be achieved by attaining supersaturation, for example, by cooling, by solvent evaporation and/or by the addition of an anti-solvent (a solvent in which the compound of formula I is poorly soluble, examples of suitable anti- solvents include heptane and isooctane). Crystallisation temperatures and times will vary depending upon the concentration of the compound in solution, the solvent system used and the method of crystallisation adopted.
  • Crystalline forms of the compound of formula I may be isolated using techniques well known to those skilled in the art, for example, by decanting, filtration or centrifuging. Similarly the crystalline form may be dried in accordance with well-known procedures.
  • Optional re-crystallisation step(s) may be performed using the same or different solvent systems to reduce further impurities, such as amorphous material, chemical impurities or to convert the crystalline into a solvated/hydrated form or an anhydrous form.
  • the compound of formula I is crystallised directly from the reaction solution or may be crystallised from a subsequent solution.
  • a further feature of the invention is a process for the production of a crystalline form of a compound of formula I which comprises crystallising the compound of formula I.
  • a crystalline form of a compound of formula I which comprises crystallising the compound of formula I.
  • a feature of the invention is a crystalline form of a compound of formula I, as described above, for use in medical therapy.
  • a pharmaceutical composition which comprises a crystalline form of a compound of formula I, as described above, in association with a pharmaceutically acceptable diluent or carrier, or the use of a crystalline form of a compound of formula I as described above in association with a pharmaceutically acceptable diluent or carrier.
  • the composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.001 mg to 50 mg of active agent mixed with an appropriate and convenient amount of excipient(s) which may vary from about 10 to about 99.9999 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 0.001 mg to about 50 mg of an active ingredient.
  • the invention also includes the use of the crystalline compound of the invention, as described above in the production of a medicament for use in: (i) treating dyslipidaemia; (ii) treating type 2 diabetes mellitus;
  • the invention also includes a method of producing an effect as defined hereinbefore or treating a disease or disorder as defined hereinbefore which comprises administering to a warm-blooded animal, preferably humans, requiring such treatment, an effective amount of a crystalline form of a compound of formula I, as described above.
  • the size of the dose for therapeutic or prophylactic purposes of a crystalline form of a compound of formula I will naturally vary according to the nature and severity of the medical condition, the age and sex of the animal or patient being treated and the route of administration, according to well known principles of medicine.
  • a crystalline form of the compound of formula I may be administered as a sole therapy or it may be administered in conjunction with other pharmacologically active agents such as an anti-diabetic, anti-hypertensive, diuretic or anti-hyperlipidaemic agent.
  • Crystalline forms prepared in accordance with the Example(s) below showed essentially the same powder X-ray diffraction patterns and/or DSC thermograms. It was clear when comparing the relevant patterns/thermograms (allowing for experimental error) that the same crystalline form had been formed.
  • DSC onset temperatures may vary in the range ⁇ 5°C (for example ⁇ 2°C)
  • powder X-ray diffraction pattern distance values may vary in the range ⁇ 5 on the last decimal place.
  • 2-(4-aminophenyl)ethanol 500 g, 3.65 mol was charged to THF (4000 ml). The mixture was cooled to 0 °C. Di-tert-butyl dicarbonate (796 g, 3.65 mol), was dissolved in THF (1000 ml). The THF solution of di-tert-butyl dicarbonate was then charged to the 2-(4- aminophenyl)ethanol in THF at 0 °C over 100 minutes. The mixture was heated to 20 °C over 3 hours and then stirred for 13 hours at 20 °C. Additional di-tert-butyl dicarbonate (41 g. 0.05 eq) was then charged portion-wise over 4 hours to take the reaction to completion .
  • the reaction was then kept at 20-25 °C for 18 hours.
  • the methylene chloride solution was then washed with water (2x4000 ml) and afterwards dried with MgSO (130 g).
  • the salt was filtered off and the solvent evaporated.
  • the remaining (2000 g) was poured out on heptane (5000 ml).
  • the crystals formed were filtered off and washed with heptane (2000 ml), yielding 1600 g (wet) (drying sample gave 1320 g ).
  • the wet substance was then re-crystallised.
  • the acidic water solution was then extracted with ethyl acetate (3x2000 ml).
  • the ethyl acetate parts were put together and washed with H 2 O (4x2000 ml).
  • the ethyl acetate solution was dried with MgS0 (90 g).
  • the salts were filtered off and washed with ethyl acetate (3x100 ml).
  • the filtrate was evaporated to dryness.
  • the oil residue (750 g) was dissolved in toluene (1750 ml).
  • DSC Differential scanning calorimetry
  • DSC of the anhydrous form showed an endotherm with an extrapolated onset temperature of ca 107 °C (ca 112 J/g).
  • Thermogravimetric analysis was performed using a Mettler Toledo TGA850 instrument and showed a decrease in mass of ca 0.15% when the compound melts, followed by decomposition.
  • DSC of the anhydrous form of the sodium salt showed an endotherm with an extrapolated onset temperature of ca 173°C (ca 54 J/g).
  • Thermogravimetric analysis was performed using a Mettler Toledo TGA850 instrument and showed a decrease in mass of ca 1% when the compound melts, followed by decomposition
  • X-ray powder diffraction analysis was performed on samples prepared according to standard methods, for example those described in: Giacovazzo, C. et al (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley and Sons, New York; Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. and Alexander, L. E. (1974), X-Ray Diffraction Procedures, John Wiley and Sons, New York.
  • X-ray analyses were performed using a Siemens D5000 diffractometer and/or a Philips X'Pert MPD diffractometer.
  • d-values of the X-ray powder diffraction patterns may vary slightly from one instrument to another and so the values quoted are not to be construed as absolute. It is reasonable to assume that a crystalline form of a compound of formula I is that which is described herein if the d-values are within + 5 on the last decimal place, especially if within + 2 on the last decimal place.
  • the unit cell and the crystal structure of the anhydrous form were determined from single crystal X-ray data.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des formes cristallines du composé acide propanoïque 3-{4-[2-(4-<tert;-butoxycarbonylaminophényl)éthoxy]phényl}-(S)-2-éthoxy représenté par la formule (I), ou un sel pharmaceutiquement acceptable de ce composé et les solvates de ce dernier. L'invention concerne également des procédés permettant de traiter au moins une maladie métabolique, plus particulièrement les maladies qui sont associées au syndrome de résistance à l'insuline, et l'utilisation de la forme cristalline du composé, ou d'un sel pharmaceutiquement acceptable de ce composé ou d'un solvate de ce dernier, dans la préparation d'un médicament destiné à un usage thérapeutique dans le cadre d'au moins une maladie métabolique. L'invention concerne également des compositions pharmaceutiques renfermant en tant qu'ingrédient actif la forme cristalline du composé ou un sel pharmaceutiquement acceptable du composé ou un solvate de ce dernier, ainsi que des procédés de préparation de la forme cristalline du composé ou d'un sel pharmaceutiquement acceptable du composé ou d'un solvate de ce dernier.
PCT/SE2000/002379 1999-12-03 2000-11-29 Forme cristalline d'acide propanoique 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(s)-2-ethoxy Ceased WO2001040165A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU20346/01A AU2034601A (en) 1999-12-03 2000-11-29 Crystalline form of 3-(4-(2-(4-tert-butoxycarbonylaminophenyl)ethoxy)phenyl)-(s) 2-ethoxy propanoic acid

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE9904417-4 1999-12-03
SE9904417A SE9904417D0 (sv) 1999-12-03 1999-12-03 Crystalline form
SE0001422-5 2000-04-17
SE0001422A SE0001422D0 (sv) 2000-04-17 2000-04-17 Crystalline form

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WO2001040165A1 true WO2001040165A1 (fr) 2001-06-07

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AR (1) AR026704A1 (fr)
AU (1) AU2034601A (fr)
WO (1) WO2001040165A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6369067B1 (en) 1997-10-27 2002-04-09 Dr. Reddy's Research Foundation Monocyclic compounds and their use in medicine: process for their preparation and pharmaceutical compositions containing them
US6531596B1 (en) 1998-10-29 2003-03-11 Dr. Reddy's Laboratories Ltd. Process for the preparation of new antidiabetic agents
US6548666B1 (en) 1997-10-27 2003-04-15 Dr. Reddy's Research Foundation Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them
US6664411B2 (en) 1997-10-27 2003-12-16 Dr. Reddy's Laboratories Limited Heterocyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
US6809095B2 (en) 1997-10-27 2004-10-26 Dr. Reddy's Laboratories Ltd. Bicyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
US6897199B2 (en) 2001-02-05 2005-05-24 Dr. Reddy's Laboratories Ltd. Pharmaceutically acceptable salts of phenoxazine and phenothiazine compounds
US6939988B1 (en) 1997-10-27 2005-09-06 Dr. Reddy's Laboratories Limited Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them
US7223881B2 (en) 1998-10-29 2007-05-29 Dr. Reddy's Laboratories Limited Process for the preparation of new antidiabetic agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062870A1 (fr) * 1998-06-04 1999-12-09 Astrazeneca Ab Nouveaux derives iii d'acide 3-aryl-2-hydroxypropionique
WO1999062871A1 (fr) * 1998-06-04 1999-12-09 Astrazeneca Ab Nouveaux derives d'acide 3-aryl propionique et analogues

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062870A1 (fr) * 1998-06-04 1999-12-09 Astrazeneca Ab Nouveaux derives iii d'acide 3-aryl-2-hydroxypropionique
WO1999062871A1 (fr) * 1998-06-04 1999-12-09 Astrazeneca Ab Nouveaux derives d'acide 3-aryl propionique et analogues

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6369067B1 (en) 1997-10-27 2002-04-09 Dr. Reddy's Research Foundation Monocyclic compounds and their use in medicine: process for their preparation and pharmaceutical compositions containing them
US6548666B1 (en) 1997-10-27 2003-04-15 Dr. Reddy's Research Foundation Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them
US6608194B1 (en) 1997-10-27 2003-08-19 Dr. Reddy's Laboratories Limited Tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
US6664411B2 (en) 1997-10-27 2003-12-16 Dr. Reddy's Laboratories Limited Heterocyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
US6809095B2 (en) 1997-10-27 2004-10-26 Dr. Reddy's Laboratories Ltd. Bicyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
US6846824B2 (en) 1997-10-27 2005-01-25 Dr. Reddy's Laboratories Ltd. Bicyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
US6939988B1 (en) 1997-10-27 2005-09-06 Dr. Reddy's Laboratories Limited Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them
US7053217B2 (en) 1997-10-27 2006-05-30 Dr. Reddy's Laboratories Limited Monocyclic compounds and their use in medicine: process for their preparation and pharmaceutical compositions containing them
US7119198B2 (en) 1997-10-27 2006-10-10 Dr. Reddy's Research Foundation Tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
US6531596B1 (en) 1998-10-29 2003-03-11 Dr. Reddy's Laboratories Ltd. Process for the preparation of new antidiabetic agents
US7223881B2 (en) 1998-10-29 2007-05-29 Dr. Reddy's Laboratories Limited Process for the preparation of new antidiabetic agents
US6897199B2 (en) 2001-02-05 2005-05-24 Dr. Reddy's Laboratories Ltd. Pharmaceutically acceptable salts of phenoxazine and phenothiazine compounds

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Publication number Publication date
AR026704A1 (es) 2003-02-26
AU2034601A (en) 2001-06-12

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